Stem cells have two distinct characteristics that distinguish them from other cell types. First, they are unspecialized and can self-renew for long periods without significant changes in their general properties. Second, under certain physiologic or experimental conditions, stem cells can be induced to differentiate into various specialized cell types. Thus, stem cells hold a great promise for regenerative medicine. There are two major types of stem cells: embryonic stem (ES) cells and adult stem cells. Adult stem cells exist in many mature tissues, such as bone marrow, muscle, fat and brain. While most studies of adult stem cells have focused on CD34+ hematopoietic stem cells, the distinct lineage of CD34− fibroblast-like mesenchymal stem cells (MSCs), especially those derived from bone marrow, have attracted significant attention from basic and clinical investigators (Chen, et al. (2006) Immunol. Cell Biol. 84:413-421; Keating (2006) Curr. Opin. Hematol. 13:419-425; Pommey & Galipeau (2006) Bull. Cancer 93:901-907). Bone marrow-derived MSCs have been shown to differentiate into several different types of tissue, such as cartilage, bone, muscle, and adipose tissue (Barry & Murphy (2004) Int. J. Biochem. Cell Biol. 36:568-584; Le Blanc & Ringden (2006) Lancet 363:1439-1441).
The promise of ES cells in regenerative medicine is extremely exciting; yet, research has not focused on the possible immunological conflict between ES cell-regenerated tissues, which are almost always allogeneic in nature, and the recipient hosts (Bradley, et al. (2002) Nat. Rev. Immunol. 2(11):859-71). There is clear evidence that immunological rejection of transplanted fetal and ES cell-derived tissues occurs very frequently (Aggarwal & Pittenger (2005) Blood 105:1815-1822; Drukker (2004) Springer Semin. Immunopathol. 26(1-2):201-13; Drukker & Benvenisty (2004) Trends Biotechnol. 22(3):136-41). On the other hand, unlike ES cells, MSCs can be highly immunosuppressive. In some studies, MSCs were found to suppress proliferation and cytokine production by T cells stimulated with mitogen or antigen (Dazzi, et al. (2006) Blood Rev. 20:161-171; Keating (2006) supra; Schenk, et al. (2006) Stem Cells 25:245-251; van Laar & Tyndall (2006) Rheumatology (Oxford) 45:1187-1193). MSCs have also been used to promote the engraftment of transplanted bone marrow and potentially ES cells (Le Blanc & Ringden (2006) Curr. Opin. Immunol. 18:586-591; Miszta-Lane, et al. (2006) Med. Hypotheses 67:909-913). In another study, no evidence of alloreactive T cells and no incidence of graft-versus-host disease (GVHD) were found when as few as 2×106 allogeneic MSCs per kg were infused along with allogeneic bone marrow into patients with metachromatic leukodystrophy, or Hurler's syndrome (Koc, et al. (2002) Bone Marrow Transplant 30:215-222). Several groups have attempted to use MSCs to prevent or treat autoimmune diseases, such as experimental autoimmune encephalomyelitis induced by MOG35-55 in C57BL/6J mice (Zappia, et al. (2005) Blood 106:1755-1761) and collagen-induced arthritis (Djouad, et al. (2005) Arthritis Rheum. 52:1595-1603). Interestingly, the immunomodulatory effect of MSCs is not always achieved (Djouad, et al. (2005) supra; Inoue, et al. (2006) Transplantation 81:1589-1595; Nauta, et al. (2006) Blood 108:2114-2120).
Elucidation of the mechanisms through which MSCs suppress immune reactions would offer better utility of these cells. In this regard, immunosuppression by MSCs has been demonstrated to involve IL-10 (Batten, et al. (2006) Tissue Eng. 12:2263-2273), TGF-β (Groh, et al. (2005) Exp. Hematol. 33:928-934), nitric oxide (Sato, et al. (2007) Blood 109:228-234), indoleamine 2,3-dioxygenase (IDO) (Meisel, et al. (2004) Blood 103(12):4619-21), and prostaglandin (PG) E2 (Aggarwal & Pittenger (2005) supra).
Nitric oxide (NO) is a rapidly diffusing gaseous molecule that is bioactive (Stamler, et al. (1992) Science 258:1898-1902). It is a free radical with one unpaired electron and is capable of affecting a diverse range of biological activities in both animals and plants.
The human and mouse genomes contain genes encoding three different NO synthases: iNOS, found in macrophages and other cell types; nNOS, found in neurons; and eNOS, found in endothelial cells. The levels of nNOS and eNOS are relatively steady, while iNOS expression is inducible and plays a major role in immune regulation. With regard to the role of NO in the immune system, besides its well established role in macrophages, recently NO has been shown to affect TCR signaling, cytokine receptor expression, and the phenotypes of T cells (Niedbala, et al. (2006) Ann. Rheum. Dis. 65 Suppl 3:iii37-iii40).
Chemokines are a superfamily of secreted small proteins that mediate leukocyte trafficking, recruitment, and recirculation during many pathophysiological processes. Chemokines are divided into subfamilies based on their conserved amino acid sequence motifs. Most chemokines have at least four conserved cysteine residues that form two intramolecular disulfide bonds. Subfamilies of chemokines and corresponding chemokine receptor are defined by the position of the first two cysteine residues on chemokines: the CXC chemokines, which bind any of the five lymphocyte-specific receptors, CXCR1-CXCR5; the CC chemokines, with 24 members that bind to CCR1-CCR11, found on most types of leukocytes; one C chemokine, termed lymphotactin, which binds to CXCR1; and one C3XC chemokine, fractalkine, which binds CXCR1. MSCs have been shown in some studies to express some chemokines and their receptors at relatively low levels (Dazzi, et al. (2006) surpa), but there is no information related to the possible role of activated T cells in the induction of chemokine expression by MSCs.